This Harvard-wide Program on Antibiotic Resistance (HPAR) proposal outlines the design and function of a novel, interdisciplinary, collaborative partnership to develop and test new validated lead compounds for changing the paradigms for treatment of multidrug resistant MRSA, VRE and now VRSA infections. Although discovery and delivery of novel and promising new compounds to the development pipeline is a major overall goal, because this is an academic effort, adding to the base of scientific knowledge that underpins the development of inhibitors for these pathogens; the understanding of resistance, and development of novel new tools for studying host-pathogen interactions and multidrug resistant pathogens are also major goals. This project is being proposed by an accomplished group of scientists with extensive experience in the biochemistry of cell wall biosynthesis and use of that information to design screens and new inhibitors; the molecular biology of model host systems and the use of those systems in novel ways for screening compounds that block the ability of bacteria to harm the host; the biology and molecular genetics of biofilm formation in model systems and the use of that information to identify biofilm disrupting agents; the pathogenesis, genetics and antibiotic resistance of enterococci; and the pathogenesis, molecular biology and clinical treatment of infection caused by multidrug resistant staphylococci. This scientific expertise is complemented by administrative experience that includes service as university Vice President for Research, and President and CEO of a research institute. The goal of the HPAR Administrative Core is to create a cohesive and well functioning whole that is greater than the sum of the individual projects. The Specific Aims of the Administrative Core are to 1) Provide program management and oversight, 2) Facilitate interactions between participants from the various components of Harvard University, 3) Provide critical infrastructure for fiscal management of the program; 4) Provide connectivity to and leverage from other Harvard-wide initiatives; and 5) Provide a single point of contact and active coordination for on-going communication with NIAID and the Program Officer, and other NIAID initiatives.